A Hedgehog-Induced Homeodomain Cascade Couples Progenitor Identity to Neuronal Diversification

How progenitor identity instructs neuronal diversification remains unclear. We uncover a homeodomain transcription factor (HDTF) cascade that links the identity of a single lamina progenitor type to the diversification of all five lamina neuron subtypes in the Drosophila visual system. Hedgehog signaling induces a pan-class HDTF—expressed across all subtypes of a neuronal class, here all lamina neurons—in progenitors, promoting cell-cycle exit. This progenitor-derived pan-class HDTF is inherited by newborn lamina neurons, where it activates subtype-specific, differentially expressed (DE) HDTFs and acts combinatorially with these DE-HDTFs to specify distinct neuronal subtypes. Loss of DE-HDTFs induces predictable, subtype-specific fate conversions—morphological and functional—reducing neuronal diversity. Strikingly, we find mouse retinal neurons express analogous pan-class and DE-HDTFs, indicating an evolutionarily conserved strategy. With HDTFs broadly expressed, our findings define a progenitor-to-newborn HDTF cascade that provides a generalizable mechanism by which progenitor identity drives neuronal diversification from a limited progenitor pool. Overall design: 4508 lamina neurons of adult female Drosophila flies were sequenced using 10x Genomics pipeline followed by scanpy analysis.